Targeting chemokine receptors in chronic inflammatory diseases: An extensive review☆
Introduction
An immune response is a complex reaction to tissue injury and infection, characterized by the classic response of rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function). The immune system consists of cells and soluble factors that mediate the reaction in order to eliminate the immune stimulus and initiate the process of immunological memory. Immunological diseases occur due to inappropriate inflammation or when the normal immune response progresses to chronic inflammation, either because of a long-term inappropriate response to stimuli (for example allergies) or because the offending agent is not removed (for example autoimmunity).
The major events in chronic inflammatory responses are continuous activating tissue resident immune cells and ongoing infiltration of circulating immune cells after which mechanisms of innate and adaptive immunity serve to neutralize and remove the inflammatory stimulus. Chemokines are a subset of chemo-attractant cytokines that promote immune cell trafficking to sites of inflammation (Moser et al., 2004).
In this review the role of chemokines and their receptors in inflammatory diseases of the airways (asthma and COPD), the intestinal tract (inflammatory bowel diseases), the joints (arthritis), the blood vessels (arteriosclerosis), the central nervous system (multiple sclerosis) and the skin (psoriasis) is discussed. Investigations of receptor-mediated and intracellular signal pathways in chemokine–receptor interactions might help to develop more effective therapeutic approaches for chronic inflammatory diseases.
Section snippets
Chemokines and their receptors
Chemokines are small (8–15 kDa) homologous proteins that are subdivided into families based on the relative position of Cysteine (Cys) residues in the NH2 terminus of the protein. The two major structural families are distinguished by the arrangement of these Cys residues, either separated by a single amino acid (CXC) or in adjacent positions (CC). Other families are the C and CX3C chemokines (Moser et al., 2004). The systemic nomenclature of the chemokines (including mouse homologs) is shown in
Chemokine receptors on immune cells
There are many different cell types in the immune system and these cells interact in a complex reaction of signaling and communication to create the overall response. The cells of the immune system derive from two types of cells in the bone marrow; myeloid stem cells and lymphoid stem cells. Myeloid cells give rise to precursor cells of the innate immune system, whereas lymphoid cells generate precursors of cells of the adaptive immune system. Cells of the innate immune system are the first
Chemokine receptors in chronic inflammatory lung diseases
The two most prevalent chronic inflammatory lung diseases are asthma and chronic obstructive pulmonary disease (COPD). These diseases are a major and increasing global health problem. Both asthma and COPD share some clinical features such as, increased airway obstruction, mucous hypersecretion, acute exacerbations and respiratory symptoms. Asthma and COPD are identified by the presence of chronic inflammation of the airways, which is controlled by the increased expression of inflammatory
Chemokine receptors in inflammatory bowel diseases
The term inflammatory bowel disease (IBD) is used to describe chronic inflammatory conditions of the gastro-intestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of IBD, and although the clinical pathological phenotypes are similar, they can be separated by different localization of the inflammation in the gastro-intestinal tract and immunological and histological patterns. CD is characterized by a transmural inflammation in any part of the gastrointestinal
Chemokine receptors in rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting symmetrically synovial tissue in polyarticular joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints leading to swelling, proliferation of synoviocytes and painful joints. The inflammatory process may result in destruction of cartilage and bone causing disability (Tak & Bresnihan, 2000). In RA synovial tissue, the infiltrating cells such as macrophages, T
Chemokine receptors in atherosclerosis
Atherosclerosis is an inflammatory disease that is characterized by lesions in the large arteries containing lipids, immune infiltrates (particularly monocytes/macrophages and T cells), connective tissue elements and debris (Libby, 2002; Glass et al., 2001; Hansson et al., 2006). This can lead to myocardial infarction in the heart and/or to ischemic stroke in the arteries. The atherosclerotic process is initiated when plasma levels of the cholesterol-rich very low-density lipoproteins and
Chemokine receptors in multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). The infiltration of mainly T cells and macrophages in the brain causes destruction of myelin sheaths of neurons and apoptosis of oligodendrocytes (the myelin forming cells). Subsequently, axonal injury occurs, resulting in impairment of conduction of signals of the affected neurons, leading to both physical and cognitive disabilities (Lassmann, 2002, Matute and Perez-Cerda, 2005, Bielecki et al., 2008
Chemokine receptors in psoriasis
Psoriasis is an inflammatory skin disease characterized by red, scaly, raised plaques. Usually, the psoriasis lesions are several centimeters in diameter and separated by normal-appearing skin (Lew et al., 2004, Lowes et al., 2007). Psoriasis involves a chronic cutaneous pathologic process, driven by interactions between infiltrating leukocytes (T cells, DCs, macrophages and neutrophils), cytokines, chemokines and keratinocytes, the cells from the epidermis. The disease is initiated or
Conclusion
Taken together, chemokines and their respective receptors play an important role in chronic inflammatory diseases, like COPD, asthma, IBD, RA, artherosclerosis, MS and psoriasis. Table 5 shows the chemokine receptors that have been identified as key players in these diseases and therefore can be considered as promising drug targets. Overall, the chemokine receptors that are present on the cell types responsible for the cause of the disease play a role in that particular disease (e.g. CXCR2 in
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This manuscript was written within the framework of the Dutch Top Institute Pharma project number T101-3.
- 1
Contributed equally to this work.